COVID-19 vaccination strategies in Africa: A scoping review of the use of mathematical models to inform policy.

OBJECTIVE: Mathematical models are vital tools to understand transmission dynamics and assess the impact of interventions to mitigate COVID-19. However, historically, their use in Africa has been limited. In this scoping review, we assess how mathematical models were used to study COVID-19 vaccination to potentially inform pandemic planning and response in Africa. METHODS: We searched six electronic databases: MEDLINE, Embase, Web of Science, Global Health, MathSciNet and Africa-Wide NiPAD, using keywords to identify articles focused on the use of mathematical modelling studies of COVID-19 vaccination in Africa that were published as of October 2022. We extracted the details on the country, author affiliation, characteristics of models, policy intent and heterogeneity factors. We assessed quality using 21-point scale criteria on model characteristics and content of the studies. RESULTS: The literature search yielded 462 articles, of which 32 were included based on the eligibility criteria. Nineteen (59%) studies had a first author affiliated with an African country. Of the 32 included studies, 30 (94%) were compartmental models. By country, most studies were about or included South Africa (n = 12, 37%), followed by Morocco (n = 6, 19%) and Ethiopia (n = 5, 16%). Most studies (n = 19, 59%) assessed the impact of increasing vaccination coverage on COVID-19 burden. Half (n = 16, 50%) had policy intent: prioritising or selecting interventions, pandemic planning and response, vaccine distribution and optimisation strategies and understanding transmission dynamics of COVID-19. Fourteen studies (44%) were of medium quality and eight (25%) were of high quality. CONCLUSIONS: While decision-makers could draw vital insights from the evidence generated from mathematical modelling to inform policy, we found that there was limited use of such models exploring vaccination impacts for COVID-19 in Africa. The disparity can be addressed by scaling up mathematical modelling training, increasing collaborative opportunities between modellers and policymakers, and increasing access to funding.

Patient-reported outcome measures for primary hyperparathyroidism: a systematic review of measurement properties.

BACKGROUND: The quality of patient-reported outcome measures (PROMs) used to assess the outcomes of primary hyperparathyroidism (PHPT), a common endocrine disorder that can negatively affect patients' health-related quality of life due to chronic symptoms, has not been rigorously examined. This systematic review aimed to summarize and evaluate evidence on the measurement properties of PROMs used in adult patients with PHPT, and to provide recommendations for appropriate measure selection. METHODS: After PROSPERO registration (CRD42023438287), Medline, EMBASE, CINAHL Complete, Web of Science, PsycINFO, and Cochrane Trials were searched for full-text articles in English investigating PROM development, pilot studies, or evaluation of at least one PROM measurement property in adult patients with any clinical form of PHPT. Two reviewers independently identified studies for inclusion and conducted the review following the Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) Methodology to assess risk of bias, evaluate the quality of measurement properties, and grade the certainty of evidence. RESULTS: From 4989 records, nine PROM development or validation studies were identified for three PROMs: the SF-36, PAS, and PHPQoL. Though the PAS demonstrated sufficient test-retest reliability and convergent validity, and the PHPQoL sufficient test-retest reliability, convergent validity, and responsiveness, the certainty of evidence was low-to-very low due to risk of bias. All three PROMs lacked sufficient evidence for content validity in patients with PHPT. CONCLUSIONS: Based upon the available evidence, the SF-36, PAS, and PHPQoL cannot currently be recommended for use in research or clinical care, raising important questions about the conclusions of studies using these PROMs. Further validation studies or the development of more relevant PROMs with strong measurement properties for this patient population are needed.

Use of extracorporeal shockwave therapies for athletes and physically active individuals: a systematic review.

OBJECTIVE: To determine the efficacy of extracorporeal shockwave therapy (ESWT) and investigate outcomes following the use of ESWT for athletes and physically active individuals. DESIGN: Systematic review. DATA SOURCES: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and searched four databases: PubMed (NLM), Embase (Elsevier), CINAHL Complete (EBSCO) and Web of Science (Clarivate). ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Included studies were randomised controlled trials, cohort and case-control studies, cases series and reports that evaluated outcomes following ESWT for athletes, physically active individuals and occupational groups requiring regular physical activity such as military cadets. RESULTS: 56 studies with 1874 athletes or physically active individuals were included. Using the Oxford level of evidence rating, included studies were 18 level I (32.1%), 3 level II (5.4%), 10 level III (17.9%), 13 level IV (23.2%) and 12 level V (21.4%). Based on the level I studies, ESWT may be effective alone in plantar fasciitis, lateral epicondylitis and proximal hamstring tendinopathy and as an adjunct to exercise treatment in medial tibial stress syndrome and osteitis pubis in athletes or physically active individuals. In most studies, athletes were allowed to continue activities and training and tolerated ESWT with minimal side effects. CONCLUSION: ESWT may offer an efficacious treatment alone or as an adjunct to concurrent exercise therapy in selected sports-related injuries and without major adverse events. Further high-level research is needed to better define the role and clinical outcomes of ESWT.

Anti-racism curricula in undergraduate medical education: A scoping review.

PURPOSE: Medical educators have increasingly focused on the systemic effects of racism on health inequities in the United States (U.S.) and globally. There is a call for educators to teach students how to actively promote an anti-racist culture in healthcare. This scoping review assesses the existing undergraduate medical education (UME) literature of anti-racism curricula, implementation, and assessment. METHODS: The Ovid, Embase, ERIC, Web of Science, and MedEdPORTAL databases were queried on 7 April 2023. Keywords included anti-racism, medical education, and assessment. Inclusion criteria consisted of any UME anti-racism publication. Non-English articles with no UME anti-racism curriculum were excluded. Two independent reviewers screened the abstracts, followed by full-text appraisal. Data was extracted using a predetermined framework based on Kirkpatrick's educational outcomes model, Miller's pyramid for assessing clinical competence, and Sotto-Santiago's theoretical framework for anti-racism curricula. Study characteristics and anti-racism curriculum components (instructional design, assessment, outcomes) were collected and synthesized. RESULTS: In total, 1064 articles were screened. Of these, 20 met the inclusion criteria, with 90% (n = 18) published in the past five years. Learners ranged from first-year to fourth-year medical students. Study designs included pre- and post-test evaluations (n = 10; 50%), post-test evaluations only (n = 7; 35%), and qualitative assessments (n = 3; 15%). Educational interventions included lectures (n = 10, 50%), multimedia (n = 6, 30%), small-group case discussions (n = 15, 75%), large-group discussions (n = 5, 25%), and reflections (n = 5, 25%). Evaluation tools for these curricula included surveys (n = 18; 90%), focus groups (n = 4; 20%), and direct observations (n = 1; 5%). CONCLUSIONS: Our scoping review highlights the growing attention to anti-racism in UME curricula. We identified a gap in published assessments of behavior change in applying knowledge and skills to anti-racist action in UME training. We also provide considerations for developing UME anti-racism curricula. These include explicitly naming and defining anti-racism as well as incorporating longitudinal learning opportunities and assessments.

Primary care perceptions of neurology and neurology services.

BACKGROUND: Neurophobia (fear of neural sciences) and evaluation of independent sector contracts in neurology have seldom been examined among general practitioners (GPs). METHODS: A questionnaire determined GPs' perceptions of neurology compared with other medical specialties. GP experiences of neurology services with independent sector companies and the local National Health Service (NHS) were compared. Areas of potential improvement in NHS neurology services were recorded from thematic analyses. RESULTS: Among 76 GPs neurology was perceived to be as interesting as other medical specialties. GPs reported less knowledge, more difficulty and less confidence in neurology compared with other medical specialties. There was a preference for a local NHS neurology service (p<0.001), which was easier to contact (p<0.001) and provided better follow-up. GPs reported that local neurology services provided better patient satisfaction. CONCLUSIONS: GPs prefer local NHS neurology services to independent sector contracts. GPs' evaluations should inform commissioning of neurology services. Combating neurophobia should be an integral part of responsive commissioning.

Dynamic vaccine blocks relapse to compulsive intake of heroin.

Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin's rapid metabolism to 6-acetylmorphine and morphine. We recently developed a "dynamic" vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin's metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin self-administration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brain-permeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6-acetylmorphine are critical players in heroin's psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance.

Stroke Laterality Bias in the Management of Acute Ischemic Stroke.

BACKGROUND: Little is known of the impact of stroke laterality on the management process and outcome of patients with acute ischemic stroke (AIS). METHODS: Consecutive patients admitted to a general hospital over 1 year with supratentorial AIS were eligible for inclusion in the study. Baseline characteristics and risk factors, delays in hospital admission, imaging, intrahospital transfer to an acute stoke unit, stroke severity and classification, length of hospital admission, as well as 10-year mortality were measured and compared among right and left hemisphere AIS patients. RESULTS: There were 141 patients (77 men, 64 women; median age 73 [interquartile range 63-79] years), There were 71 patients with left hemisphere AIS and 70 with right hemisphere AIS. Delays to hospital admission from stroke onset to neuroimaging were similar among right and left hemisphere AIS patients. Delay in transfer to an acute stroke unit (ASU) following hospital admission was on average 14 hours more for right hemisphere compared to left hemisphere AIS patients (P = .01). Laterality was not associated with any difference in 10-year survival. CONCLUSIONS: Patients with mild and nondominant AIS merit particular attention to minimize their intrahospital transfer time to an ASU.

A quality improvement programme with a specialist nurse in a neurovascular clinic.

AIMS AND OBJECTIVES: To measure the impact of a quality improvement programme with a stroke specialist nurse and increased capacity at neurovascular clinics. BACKGROUND: Transient ischaemic attack and minor stroke are medical emergencies prompting urgent assessment and treatment. Delays in specialist assessment and management are frequent and may increase stroke risk. DESIGN: Pre- and post evaluation of intervention. METHODS: All patients referred to a neurovascular clinic were recorded during two phases: 2006-2008 and 2010-2012. For the 2010-2012 period, a stroke specialist nurse contacted all patients with appointment details, provided driving advice and asked for an eyewitness to attend the clinic. Diagnosis, delay in specialist assessment, prevalence of transient ischaemic attack/minor stroke as confirmed at the clinic and compliance with UK driving regulations were measured and compared before and after this intervention. RESULTS: A total of 1327 patients were assessed in the two study phases. Referrals to the neurovascular service increased without a decrease in the prevalence of transient ischaemic attack/minor stroke. Delays from clinical event to assessment were decreased for referrals from 36·5-13 days, and adherence to the UK driving restrictions improved for confirmed transient ischaemic attack/minor stroke patients from 61-94%. Fewer patients failed to attend a neurovascular appointment arranged by the stroke specialist nurse than those who failed a general neurology appointment arranged by partial booking. CONCLUSIONS: This quality improvement programme reduced delays for all referred patients, improved compliance with driving regulations and demonstrated efficient use of neurovascular clinic spaces. Increasing local capacity may unmask more transient ischaemic attack/minor stroke patients. RELEVANCE TO CLINICAL PRACTICE: A stroke nurse can help improve the efficiency of a neurovascular clinic and improve patient safety with driving advice.

Communication Preferences During Pregnancy Care Among Patients With Primary Spanish Language: A Scoping Review.

BACKGROUND: Qualified language service providers (QLSPs)-professional interpreters or multilingual clinicians certified to provide care in another language-are critical to ensuring meaningful language access for patients. Designing patient-centered systems for language access could improve quality of pregnancy care. OBJECTIVE: We synthesized and identified gaps in knowledge about communication preferences during pregnancy care among patients with Spanish primary language. METHODS: We performed a scoping review of original research studies published between 2000 and 2022 that assessed communication preferences in Spanish-speaking populations during pregnancy care. Studies underwent title, abstract, and full-text review by three investigators. Data were extracted for synthesis and thematic analysis. RESULTS: We retrieved 1,539 studies. After title/abstract screening, 36 studies underwent full-text review, and 13 of them met inclusion criteria. Two additional studies were included after reference tracing. This yielded a total of 15 studies comprising qualitative (n = 7), quantitative (n = 4), and mixed-methods (n = 4) studies. Three communication preference themes were identified: language access through QLSPs (n = 7); interpersonal dynamics and perceptions of quality of care (n = 9); and information provision and shared decision-making (n = 8). Although seven studies reported a strong patient preference to receive prenatal care from Spanish-speaking clinicians, none of the included studies assessed clinician Spanish language proficiency or QLSP categorization. CONCLUSIONS: Few studies have assessed communication preferences during pregnancy care among patients with primary Spanish language. Future studies to improve communication during pregnancy care for patients with primary Spanish language require intentional analysis of their communication preferences, including precision regarding language proficiency among clinicians.

Pregnancy Care Utilization, Experiences, and Outcomes Among Undocumented Immigrants in the United States: A Scoping Review.

BACKGROUND: Undocumented immigrants face many barriers in accessing pregnancy care, including language differences, implicit and explicit bias, limited or no insurance coverage, and fear about accessing services. With the national spotlight on maternal health inequities, the current literature on undocumented immigrants during pregnancy requires synthesis. OBJECTIVE: We aimed to describe the literature on pregnancy care utilization, experiences, and outcomes of undocumented individuals in the United States. METHODS: We performed a scoping review of original research studies in the United States that described the undocumented population specifically and examined pregnancy care utilization, experiences, and outcomes. Studies underwent title, abstract, and full-text review by two investigators. Data were extracted and synthesized using descriptive statistics and content analysis. RESULTS: A total of 5,940 articles were retrieved and 3,949 remained after de-duplication. After two investigators screened and reviewed the articles, 29 studies met inclusion criteria. The definition of undocumented individuals varied widely across studies. Of the 29 articles, 24 showed that undocumented status and anti-immigrant policies and rhetoric are associated with decreased care utilization and worse pregnancy outcomes, while inclusive health care and immigration policies are associated with increased prenatal and postnatal care utilization as well as improved pregnancy outcomes. CONCLUSIONS: The small, heterogeneous literature on undocumented immigrants and pregnancy care is fraught with inconsistent definitions, precluding comparisons across studies. Despite areas in need of further research, the signal among published studies is that undocumented individuals experience variable access to pregnancy care, heightened fear and stress regarding their status during pregnancy, and worse outcomes compared with other groups, including documented immigrants.

Communications for US Populations With Limited English Proficiency During Infectious Disease Outbreaks: A Scoping Review.

The COVID-19 pandemic has highlighted the need for research about communicating with populations who have limited English proficiency in the United States during infectious disease outbreaks. These populations have experienced significantly worse health outcomes during emergencies, including the COVID-19 pandemic, and evidence-based risk communications are critical to protecting their health. To support improved development of emergency communications for these communities, we conducted a scoping review that examined the extent of research available, with an intent to identify which communications topics are covered in the literature and where research gaps exist. Following the JBI framework, with reporting guided by the PRISMA extension for scoping reviews, 6 electronic databases were systematically searched in October 2022. The inclusion criteria for articles selected were: data collected between 2009 and 2022, published in English, and focused on communications pertaining to emergency infectious disease outbreaks (eg, H1N1 influenza, Zika virus, COVID-19) for populations with limited English proficiency. Of 2,049 articles identified through the search, 31 met the inclusion criteria and were selected for review. We identified major limitations in the evidence base: a majority of studies were conducted only among Spanish speakers or during the COVID-19 pandemic, and most used qualitative or nonrandom samples. Most studies documented basic language barriers in communications, but there was little exploration of more nuanced barriers, such as cultural relevance or social context. Ahead of future outbreaks, more research is urgently needed to examine the information landscapes of populations with limited English proficiency, to inform the development of more effective communications strategies from public health institutions and others.

A Pilot Study of Polysubstance Use Sequences across the Lifespan among Assiniboine and Sioux People Who Use Injection Drugs.

Compared with other racial/ethnic groups in the United States, American Indians/Alaska Natives have the highest rates of acute Hepatitis C Virus (HCV) infection, the highest HCV-related mortality, and one of the fastest climbing rates of drug overdose deaths involving stimulants. In this pilot study, a life history calendar was administered to Indigenous people who use injection drugs (IPWIDs) to understand sequences of polysubstance use across the lifespan. 40 IPWIDs completed a questionnaire and life history calendar. Social sequence analysis was used to examine patterns in sequential phenomena among substances reported over years of the lifespan. Most participants (55%) began injecting substances before the age of 21, 62.5% shared syringes with others, and 45% had ever been diagnosed with HCV. An appreciably large increase in the use of stimulants occurred between the year prior to and following injection initiation (33% to 82%). A three-cluster solution distinguished younger IPWIDs transitioning into polysubstance use involving stimulants and/or narcotic analgesics from adults using narcotic analgesics with stimulants over longer periods of time, and adults most focused on stimulant use over time. Findings from this pilot study contribute to an understanding of how methamphetamine injection plays a role in the HCV epidemic among IPWIDs.

Stroke scan agnosia - What radiologists may not see.

OBJECTIVE: Neuroimaging helps neurologists make accurate diagnoses. We used a multidisciplinary review system to search for perceptual discrepancies in stroke lesions. We sought to identify recurrent pitfalls in the detection of neuroimaging stroke lesions. PATIENTS AND METHODS: Patients were selected from a neuroimaging database of second opinions if cerebrovascular lesions had been missed at initial reporting. Patient demographics, scanning modality and stroke type were recorded. RESULTS: A neuroradiologist second opinion was provided for 1336 patients. Forty-four patients, 18 women and 26 men, mean age 59.9 (SD 14.2) years, were identified in whom a vascular lesion was not detected on initial reporting. The lesions included cerebellar infarcts in 17 patients (bilateral in 7), pontine infarction/ischaemia (n=5), pontine and cerebellar lesions (n=1) and spinal infarction (n=1). Supratentorial infarction occurred in 10 patients of which 3 were thalamic infarcts. Vessel abnormalities were present in 8 patients (hyperdense vessel n=3, dissection n=3, middle cerebral artery occlusion on CTA n=1 and cerebral venous sinus thrombosis n=1). Convexity subarachnoid hemorrhage was missed and a subdural hematoma was not identified in one patient. In 10 (23 %) patients the missed lesions occurred solely on CT brain scanning. The missed lesions were symptomatic in 28 (64 %) patients and presentations were acute in 14 (32 %) patients. CONCLUSION: Some cerebrovascular lesions are prone to perceptual errors with CT and MRI brain scanning. Radiologists and neurologists should be aware that posterior fossa lesions (particularly in the cerebellum and pons) and hyperdense vessel signs may be missed. Better identification of radiological cerebrovascular lesions should enhance management of acute and chronic stroke patients.

Immunoneutralization of agmatine sensitizes mice to micro-opioid receptor tolerance.

Systemically or centrally administered agmatine (decarboxylated arginine) prevents, moderates, or reverses opioid-induced tolerance and self-administration, inflammatory and neuropathic pain, and sequelae associated with ischemia and spinal cord injury in rodents. These behavioral models invoke the N-methyl-D-aspartate (NMDA) receptor/nitric-oxide synthase cascade. Agmatine (AG) antagonizes the NMDA receptor and inhibits nitric-oxide synthase in vitro and in vivo, which may explain its effect in models of neural plasticity. Agmatine has been detected biochemically and immunohistochemically in the central nervous system. Consequently, it is conceivable that agmatine operates in an anti-glutamatergic manner in vivo; the role of endogenous agmatine in the central nervous system remains minimally defined. The current study used an immunoneutralization strategy to evaluate the effect of sequestration of endogenous agmatine in acute opioid analgesic tolerance in mice. First, intrathecal pretreatment with an anti-AG IgG (but not normal IgG) reversed an established pharmacological effect of intrathecal agmatine: antagonism of NMDA-evoked behavior. This result justified the use of anti-AG IgG to sequester endogenous agmatine in vivo. Second, intrathecal pretreatment with the anti-AG IgG sensitized mice to induction of acute spinal tolerance of two micro-opioid receptor-selective agonists, [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin and endomorphin-2. A lower dose of either agonist that, under normal conditions, produces moderate or no tolerance was tolerance-inducing after intrathecal pretreatment of anti-AG IgG (but not normal IgG). The effect of the anti-AG IgG lasted for at least 24 h in both NMDA-evoked behavior and the acute opioid tolerance. These results suggest that endogenous spinal agmatine may moderate glutamate-dependent neuroplasticity.

Supraspinally-administered agmatine attenuates the development of oral fentanyl self-administration.

The decarboxylation product of arginine, agmatine, has effectively reduced or prevented opioid-induced tolerance and dependence when given either systemically (intraperitoneally or subcutaneously) or centrally (intrathecally or intracerebroventricularly). Systemically administered agmatine also reduces the escalation phase of intravenous fentanyl self-administration in rats. The present study assessed whether centrally (intracerebroventricular, i.c.v.) delivered agmatine could prevent the development of fentanyl self-administration in mice. Mice were trained to respond under a fixed-ratio 1 (FR1) schedule for either fentanyl (0.7 microg/70 microl, p.o.) or food reinforcement. Agmatine (10 nmol/5 microl), injected i.c.v. 12-14 h before the first session and every other evening (12-14 h before session) for 2 weeks, completely attenuated oral fentanyl self-administration (but not food-maintained responding) compared to saline-injected controls. When agmatine was administered after fentanyl self-administration had been established (day 8) it had no attenuating effects on bar pressing. This dose of agmatine does not decrease locomotor activity as assessed by rotarod. The present findings significantly extend the previous observation that agmatine prevents opioid-maintained behavior to a chronic model of oral fentanyl self-administration as well as identifying a supraspinal site of action for agmatine inhibition of drug addiction.

The value of neuroimaging team meetings for patients in a district general hospital.

Neuroradiologists provide quality-assured neuroimaging -reports. We developed the use of a neuroimaging team meeting to provide second-opinion reporting by neuroradiologists on neuroimaging that had previously been reported by general -radiologists. Neuroimaging from selected patients was reviewed at the meeting. Where there were discrepancies between an original report from a general radiologist and the report obtained from the meeting involving a neuroradiologist, we classified the discrepancies, recorded the scan modality -involved and used the data to assess temporal trends in discrepancy rates. Over 4 years, 562 patients (312 women, 250 men, mean age 50.6 [SD 17.3] years) were studied. Agreement occurred for 396 (70.5%) patients. Discrepancies that were not clinically important occurred for 60 (10.7%) patients. Clinically important discrepancies were found for 106 (18.9%) patients: missed lesions for 47 (8.3%) patients and misinterpretations for 59 (10.5%) patients. Cerebrovascular disease was the most common reason for a recommendation of neuroimaging review at a meeting. Scan modality did not influence the frequency of discrepancies. Discrepancy rates decreased with time (chi-squared test for linear trend p=0.015), while the frequency of neuroradiologists' recommendations for new investigations was stable at one in seven patients. Neuroimaging team meetings can facilitate improvements in neurology diagnoses.

High-Frequency Stimulation of the Subthalamic Nucleus Blocks Compulsive-Like Re-Escalation of Heroin Taking in Rats.

Opioid addiction, including addiction to heroin, has markedly increased in the past decade. The cost and pervasiveness of heroin addiction, including resistance to recovery from addiction, provide a compelling basis for developing novel therapeutic strategies. Deep brain stimulation may represent a viable alternative strategy for the treatment of intractable heroin addiction, particularly in individuals who are resistant to traditional therapies. Here we provide preclinical evidence of the therapeutic potential of high-frequency stimulation of the subthalamic nucleus (STN HFS) for heroin addiction. STN HFS prevented the re-escalation of heroin intake after abstinence in rats with extended access to heroin, an animal model of compulsive heroin taking. STN HFS inhibited key brain regions, including the substantia nigra, entopeduncular nucleus, and nucleus accumbens shell measured using brain mapping analyses of immediate-early gene expression and produced a robust silencing of STN neurons as measured using whole-cell recording ex vivo. These results warrant further investigation to examine the therapeutic effects that STN HFS may have on relapse in humans with heroin addiction.

Interleukin-1alphabeta gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain.

The pro-inflammatory cytokine interleukin-1 (IL-1) has been implicated in both inflammatory processes and nociceptive neurotransmission. To further investigate the role of IL-1 in different pain states, gene-disrupted mice lacking both IL-1alpha and IL-1beta genes (IL-1alphabeta (-/-)) were characterized in inflammatory, neuropathic, and post-operative pain models. IL-1alphabeta (-/-) mice showed normal sensorimotor function as measured by the rotorod assay compared to control mice (BALB/c). Acute and persistent formalin-induced nocifensive behaviors were reduced by 20% in IL-1alphabeta (-/-) mice as compared to control mice. IL-1alphabeta (-/-) mice also showed reduced inflammatory thermal and mechanical hyperalgesia compared to controls following the intraplantar administration of carrageenan or complete Freund's adjuvant (CFA). The duration of inflammatory hyperalgesia was shortened in IL-1alphabeta (-/-) mice versus controls in the CFA model. In contrast, deletion of IL-1alphabeta did not change the extent or the duration of post-operative pain developing after skin incision of the hind paw. Finally, time to onset, duration, and magnitude of mechanical allodynia were reduced in two models of neuropathic pain, spinal nerve L5-L6 ligation and chronic constriction injury of the sciatic nerve, in IL-1alphabeta (-/-) mice versus controls. These results demonstrate that IL-1alphabeta modulates both the generation and the maintenance of inflammatory and chronic neuropathic pain and that IL-1 may modulate nociceptive sensitivity to a greater extent in conditions of chronic as compared to acute pain.

ABT-594 (a nicotinic acetylcholine agonist): anti-allodynia in a rat chemotherapy-induced pain model.

ABT-594 ((R)-5-(2-azetidinylmethoxy)-2-chloropyridine) represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic acetylcholine receptors. The present study characterized the effects of ABT-594 in a rat chemotherapy-induced neuropathic pain model, where it attenuated mechanical allodynia with an ED50 = 40 nmol/kg (i.p.). This anti-allodynic effect was not blocked by systemic (i.p.) pretreatment with naloxone but was blocked completely with mecamylamine. Pretreatment with chlorisondamine (0.2-5 micromol/kg, i.p.) only partially blocked the effects of ABT-594 at the higher doses tested. In contrast, central (i.c.v.) pretreatment with chlorisondamine completely blocked ABT-594's anti-allodynic effect. Taken together, the data demonstrate that ABT-594 has a potent anti-allodynic effect in the rat vincristine model and that, in addition to its strong central site of action, ABT-594's effects are partially mediated by peripheral nicotinic acetylcholine receptors in this animal model of chemotherapy-induced neuropathic pain.